The dopamine D2 receptor (D2R)-expressing medium spiny neurons (D2-MSN) in the striatum project to the GABAergic neurons in the globus pallidus (GP), forming an important link in the basal ganglia motor control circuit. When D2-MSNs fire spikes, their target GP neurons are inhibited. The striatopallidal axon terminals express D2Rs that inhibit GABA release and thus reduce the inhibition of GP neurons. In Parkinson's disease (PD), due to the severe dopamine loss, this D2R-mediated negative control at the striatopallidal axon terminals is reduced or lost. At the same time, dopamine receptors including D2Rs become supersensitive as a homeostatic response and may even mediate the therapeutic effects of dopaminergic treatments for PD. However, despite its importance, D2R supersensitivity at the striatopallidal axon terminals has not been studied and the functional consequences also remain unknown. This proposal is aimed at filling these two knowledge gaps. Based on the literature and our pilot data, we hypothesize that (1) presynaptic D2Rs at the striatopallidal axon terminals are supersensitized following dopamine depletion, and (2) during dopaminergic treatment, the supersensitive presynaptic D2Rs disinhibit GP neurons in a supersensitive manner. We will test these ideas using quantitative electrophysiological methods and 2 mouse models with consistent DA loss. Results from this project will determine if the presynaptic D2R-mediated inhibition of the striatopallidal projection is supersensitized under a DA-depleted (parkinsonian) condition. If proven, this is a new mechanism that can compensate for the loss of dopamine in PD, and the presynaptic D2Rs on the striatopallidal axon terminals may also be a target of the dopaminergic treatments for PD.

Public Health Relevance

Parkinson's disease is a common debilitating movement disorder arising from dopamine loss and the associated abnormalities in the brain movement control circuit. Medium spiny neurons in the striatum project to and inhibit the globus pallidus, forming an important link in the movement control circuit. This proposal will test our idea that dopamine D2 type receptors on the axon terminals of medium spiny neurons are supersensitive under parkinsonian condition that can compensate for the lost dopamine and potentially serve as a target of the dopaminergic treatments for Parkinson's disease.